This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.